This invention relates to a novel contraceptive method employing a competitive progesterone antagonist and to novel progesterone antagonists useful therein.
By inhibiting the formation of endometrial glands and epithelium growth, the implantation of a fertilized egg in the uterus is rendered impossible (inhibition of the uterine receptivity). The employment of competitive progesterone antagonists according to the invention can thus be used for contraception in the female.
RU 486 (11xcex2-[4-N,N-(dimethylamino)phenyl]-17xcex2-hydroxy-17xcex1-propinyl-estra-4,9(10)-dien-3-one; EP-A-0057115) and other 11xcex2-aryl or 11xcex2,19-arylene-substituted steroids are compounds which can displace progesterone and the glucocorticoids from their respective receptors. These substances are pharmacologically distinguished by strong progesterone- and glucocorticoid-antagonistic effects. These properties determine their previously practiced therapeutic uses. RU 486 is useful, e.g., as a progesterone antagonist for therapeutic termination of pregnancy and also as a glucocorticoid antagonist for treatment of Cushing""s syndrome in the wake of a pathologically increased secretory activity of the suprarenal cortex. The abortive dose of RU 486 is 200-600 mg in the female.
It has also long been known that competitive progesterone antagonists are able to inhibit ovulation in various animal species and in the human female. (Collins et al., xe2x80x9cBlockade of the spontaneous mid-cycle gonadotropin surge in monkeys by RU 486; A progesterone antagonist or agonistxe2x80x9d, J. Clin. Metab., 63:1270-1276 (1986);
Croxatto, H. B., xe2x80x9cSalvatierra 1990 Cyclic use of anti-gestagens for fertility controlxe2x80x9d, IIIrd International Symposium on Contraception, Heidelberg, Jun. 19-23, 1990;
Danford et al., xe2x80x9cContraceptive potential of RU 486 by ovulation inhibition. III. Preliminary observations on once weekly administrationxe2x80x9d, Contraception 40: 195-200 (1989);
Kekkonen et al., xe2x80x9cLxc3xa4hteoenmxc3xa4ki P 1990 Interference with ovulation by sequential treatment with the antiprogesterone RU 486 and synthetic progestinxe2x80x9d, Fertil Steril [Fertile Sterile] 53,4747;
Puri et al., xe2x80x9cGonadal and pituitary responses to progesterone antagonist ZK 98 299 during the follicular phase of the menstrual cycle in bonnet monkeysxe2x80x9d, Contraception 39, 2: 227-243 (1989);
Puri et al., xe2x80x9cContraceptive potential of a progesterone antagonist ZK 98 734: Effect on folliculogenesis, ovulation and corpus luteum function in bonnet monkeysxe2x80x9d. In Moudgal et al., (eds) (1990);
U.S. Pat. No. 4,764,513 teaches that the receptivity of the endometrium for implantation (implantation window) can be shifted (delayed) by administering a competitive progesterone antagonist to a female to increase the likelihood of successful implantation of an in vitro fertilized egg.
11xcex2,19-o-Phenylene-bridged steroids, which exhibit especially strong competitive progesterone-antagonistic effectiveness in the case of considerably reduced anti-glucocorticoid activity relative to the comparison compound 11xcex2-(4-dimethylaminophenyl)-17xcex2-hydroxy-17xcex1-(propin-1-yl)-4,9(10)-estradien-3-one (RU 486; EP-A-0 057 115), are described for the first time in U.S. Pat. No. 5,095,129. The novel compounds of this invention (Compounds I and II) fall within the scope of the generic formula of U.S. Pat. No. 5,095,129, but are not disclosed therein by name or by example.
The dose of a competitive progesterone antagonist having an ovulation inhibition effect depends greatly on the species thereof employed. In the case of RU 486, it is 50-100 mg in the human female. (Croxatto et al.; loc. cit., Ledge et al. (1992) Inhibition of ovulation using very low dose mifepristone; Abstract: Second Congress of the European Society of Contraception. RU 486 shows little or no dissociation of its central and endometrial effects in humans (Ledge W. L. et al., Terra Symposium on Progesterone Antagonists, May 25-29, 1992, Mohouk, N.Y.).
An xe2x80x9cLH+2xe2x80x9d treatment for implantation inhibition has been proposed (Swahn et al., xe2x80x9cThe effect of RU 486 administration during the early luteal phase on bleeding pattern, hormonal parameters and endometrium,xe2x80x9d Human Reproduction 5, 4:402-408 (1990)): 2 days after the LH peak (LH=Luteinizing Hormone) in the menstrual cycle (occurrence of the LH peak corresponds to the time of ovulation) of the female (i.e., thus on day 14, 15 or 16), an ovulation-inhibiting dose of RU 486 is administered one time. The active compound is thus administered only after the time of ovulation in the luteal phase of the menstrual cycle (luteal contraception).
It was only recently reported that an endometrial desynchronization in the female without hormonal changes (progesterone and estradiol concentrations) can be achieved by the competitive progesterone antagonist RU 486, when the latter was administered on day 5 and day 8 after the occurrence of the LH peak in the menstrual cycle (dosage in each case 10 mg, peroral) (Kettel et al., 1992). Reliable conception without ovulation inhibition cannot be achieved if a competitive progesterone antagonist is administered only after LH peaks in the menstrual cycle is achieved.
It has now been found that in accordance with this invention, competitive progesterone antagonists are capable, at a dosage regime which does not inhibit ovulation or induce abortion, of inhibiting the formation of endometrial glands in the proliferation phase as well as the function of the glands in the luteal phase of the menstrual cycle, thereby achieving contraception, if the administration of the dose takes place at least once before and optionally also after the occurrence of the LH peak.
In a method aspect, this invention relates to a method of contraception in a female, which comprises administering thereto during the follicular phase of her menstrual cycle and optionally also in the luteal phase thereof an amount of a competitive progesterone antagonist, which is less than an ovulation-inhibiting and less than an abortion-inductive dose and which is effective to inhibit the formation of endometrial glands, which glands are a requirement for the implantation of a fertilized egg in the uterus.
In a composition aspect, this invention relates to an 11xcex2,19-o-phenylene-17xcex2-hydroxy-17xcex1-(3-hydroxyprop-1(Z)-enyl)-4-androsten-3-one of the formula: 
wherein R is 
In another composition aspect, this invention relates to a pharmaceutical composition comprising in admixture with a pharmaceutically acceptable carrier, an amount per unit dosage of a competitive progesterone antagonist which is less than an ovulation-inhibiting and less than an abortion-inductive dose and which is effective to inhibit the formation of endometrial glands and epithelium growth.
In the proliferation phase, an estrogen-induced formation of the secretory glands in the endometrium occurs in the normal menstrual cycle, while in the luteal phase (also designated as the secretion phase), the secretory activity of the glands is induced by progesterone. The described effect of the competitive progesterone antagonists in the proliferation phase, i.e., before ovulation, thus is not inherently based on a progesterone inhibition effect, since the proliferation of the endometrial glands is estrogen-dependent. Further, the progesterone concentrations in the blood in the proliferation phase of the menstrual cycle are very low. By the use of competitive progesterone antagonists according to the invention, a selective inhibition of the uterine receptivity is achieved without adversely influencing the menstrual cycle and at doses too low to induce abortion if ovum implant has already occurred.
The ability to achieve contraception at lower than abortion-inducing doses and ovulation inhibiting doses is a very important consideration for some human females who are opposed to abortion or are concerned about the long-term medical effects of ovulation inhibition.
A decisive advantage of the use proposed here exists in the very high contraceptive reliability of the progesterone antagonist employed, since the endometrium is not capable to receive a fertilized egg when a respectively very low dosage of the competitive progesterone antagonist is administered before and optionally after the ovulation. An implantation is also not to be ruled out in the proliferation phase of the normal menstrual cycle. Since the endometrial glandular secretions are essential for endometrial receptivity, a successful implantation is impossible in the case of an atrophy of the endometrial glands and epithelium. As a result, contraceptive reliability is also assured in females with an irregular menstrual cycle.
Two novel competitive progesterone antagonists, viz., 11xcex2,19-[4-(4-cyanophenyl)-o-phenylene]-17xcex2-hydroxy-17xcex1-(3-hydroxyprop-1(Z)-enyl)-4-androsten-3-one (I) and 11xcex2,19-[4-(3-pyridinyl)-o-phenylene]-17xcex2-hydroxy-17xcex1-(3-hydroxyprop -1(Z)-enyl)-4-androsten-3-one(II) have surprisingly pronounced peripherally selective effectiveness, i.e., the effect of compounds I and II on the endometrium is very greatly pronounced, while at the same dose, at most only a slight central effect is observed on the hypophysial-ovarian axis.
Such competitive progesterone antagonists can also be designated as dissociated, since at a specific threshold dose, although changes of the endometrium are observed, ovulation (central effect) is not inhibited. The ratio of ovulation-inhibiting dose and implantation inhibiting dose (dissociation factor) (as determined in the rat after peroral administration) can be used as a measurement of the dissociation. This ratio varies from species to species but is at least about 30 or higher in a dissociated or competitive progesterone antagonist.
An advantage of dissociated or competitive progesterone antagonists lies in the fact that they can be administered at doses high enough to achieve endometrial effects without inhibiting ovulation. As a result, a normal menstrual cycle is maintained.
The competitive progesterone antagonists are preferably administered as individual spaced dosage units, e.g., preferably at 4 to 10 days in regular intervals, e.g., every week of the menstrual cycle, each at a dose which is insufficient to inhibit ovulation or to induce abortion if implantation has already occurred. On the other hand, a similar effect on endometrial receptivity can be achieved with lower once-daily oral doses. The use of slow release systems (microcrystalline suspensions, transdermal patches and subcutan implants) is also possible, provided the amount of progesterone antagonist released therefrom is sufficient to inhibit ovum implantation during the predicted life of the system but lower than the dose which interferes with any ovulations which would otherwise have occurred during that period of time.
The above-described use of competitive progesterone antagonists is evidenced by tests performed with Onapriston [11xcex2-(4-dimethylaminophenyl)-17xcex1-hydroxy-17xcex2-(3-hydroxypropyl)-13xcex1-methyl -4,9-gonadien-3-one; EP-A-0129499], a typically competitive progesterone antagonist, on adult, female bonnet monkeys (Macaca radiata).
The test design is set forth below:
Observations relative to the changes of the endometrium and the hormone level:
Table 1 shows that both the length of the cycle and the menstrual period relative to the control group are not changed by the treatment according to the invention.
The estradiol and progesterone levels clearly show that the folliculogenesis and ovulation has occurred normally in all animals: normal preovulatory estradiol peak, normal progesterone level in the luteal phase (FIG. 1).
The histology shows that in contrast to control animals, the endometrium was atrophied in both treatment groups. Especially affected were the endometrial glands: atrophic and inactive glands with an increase of the stromal tissue.
The above-described observations clearly show that competitive progesterone antagonists are suitable for contraception (implantation inhibition), at individual doses having a non-ovulation-inhibiting effect as well as a non-abortive effect in each individual dosage unit, provided the administration of the dosage units takes place before and optionally also after ovulation within each menstrual cycle.
As competitive progesterone antagonists, all compounds are suitable which have a great affinity to the gestagen receptor (progesterone receptor) and exhibit no gestagen activity of their own. For example, the following steroids are suitable:
11xcex2-[(4-N,N-Dimethylamino)-phenyl]-17xcex2-hydroxy-17xcex1-propinyl-4,9(10)-estradien-3-one (RU-38486),
11xcex2-[(4-N,N-dimethylamino)-phenyl]-17xcex2-hydroxy-18-methyl-17xcex1-propinyl-4,9(10)-estradien-3-one and
11xcex2-[(4-N,N-dimethylamino)-phenyl]-17axcex2-hydroxy-17axcex1-propinyl-D-homo-4,9(10),16-estratrien-3-one (all disclosed in EP-A-0 057 115);
11xcex2-p-methoxyphenyl-17xcex2-hydroxy-17xcex1-ethinyl-4,9(10)-estradien-3-one (Steroids 37 (1981), 361-382), and
11xcex2-(4-acetylphenyl)-17xcex2-hydroxy-17xcex1-(prop-1-inyl)-4,9(10)-estradien-3-one (EP-A 0 190 759); and
the 11xcex2-aryl-14xcex2-estradienes and estratrienes described in EP-A 0 277 676, the 19,11xcex2-bridged steroids, which are the subject of U.S. Pat. No. 5,095,129, the 11xcex2-aryl-6-alkyl (or 6-alkenyl or 6-alkinyl)-estradienes and pregnadienes known from EP-A 0 289 073 and the 11xcex2-aryl-7-methyl (or 7-ethyl)-estradienes known from EP-A 0 321 010 as well as the 10xcex2-H steroids of EP-A 0 404 283. This list is not complete as other competitive progesterone antagonists described in the above-mentioned publications as well as those of publications not mentioned here are also suitable.
For use according to this invention, especially suitable are those competitive progesterone antagonists which are peripherally selectively effective, i.e., in which the endometrial effect is pronounced, at a dose at which at most only a slight central effect is observed on the hypophysial-ovarian axis.
Such competitive progesterone antagonists can also be designated as dissociated, since at a specific threshold dose, changes of the endometrium are observed, but the ovulation (central effect) is not inhibited. The ratio of ovulation-inhibiting and implantation inhibiting (dissociation factor) doses can be used as a measurement for the dissociation. It varies depending on the species and is about 30 or more for a dissociated competitive progesterone antagonist (in the rat after peroral administration) to be used according to the invention.
The advantage of dissociated competitive progesterone antagonists being used according to this invention lies in the fact that they can be administered at higher doses to ensure achieving the necessary endometrial effects without ovulation being inhibited; i.e., the xe2x80x9cnormalxe2x80x9d course of the menstrual cycle is maintained.
The competitive progesterone antagonists can be administered, for example, locally, topically, enterally, transdermally or parenterally. Oral administration is preferred.
For the preferred oral administration, especially tablets, coated tablets, capsules, pills, suspensions or solutions are suitable, which can be produced in the usual way with the additives and vehicles usual in galenicals. For local or topical use, for example, vaginal suppositories, vaginal gels, implants, vaginal rings or transdermal systems such as skin plasters are suitable.
A dosage unit typically contains about 0.25 to 50 mg of 11xcex2-[(4-N,N-dimethylamino)-phenyl]-17xcex1-hydroxy-17xcex2-(3-hydroxypropyl)-13xcex1-methyl-4,9(10)-gonadien-3-one or a biologically equivalent amount of another competitive progesterone antagonist.
If the administration of the pharmaceutical agent produced according to the invention takes place by an implant, a vaginal ring or a transdermal system, these administration systems have to be designed so that the dose of the competitive progesterone antagonist released daily in this range is 0.25 to 50 mg.
The dose of a competitive progesterone antagonist to be administered according to the invention is below the ovulation inhibiting as well as abortion-inductive dose range of the progesterone antagonist in question.
In general, 0.25-20 mg is administered per one-time dose; especially and specifically in the use of peripherally selective competitive progesterone antagonists, 0.5-50 mg per one-time administration can be dosed, since the peripherally selective substances permit a far higher dosage without resulting in ovulation inhibition. The term, xe2x80x9cone-timexe2x80x9d dose or administration includes an administration system continuously releasing the competitive progesterone antagonist at a rate corresponding to a 0.25-20 mg daily dose or a 0.5-50 mg single dose.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.
The entire disclosures of all applications, patents and publications, if any, cited above and below, and of German priority applications P 42 16 003.0 and P 42 16 004.9, are hereby incorporated by reference.